ABSTRACT Fatigue is the most common and distressing symptom among breast cancer survivors and can persist for years after treatment, even in those clinically disease-free. Most studies among cancer survivors have evaluated the prevalence of fatigue using a cross-sectional design with limited longitudinal follow-up and none of the published studies to date have data on subjects before diagnosis. We propose to utilize the prospective Nurses'Health Study (NHS) cohort, which includes data on subjects before and after cancer diagnosis as well as a cancer-free comparison group, to evaluate the prevalence and trajectory of fatigue among breast cancer survivors not currently on treatment and the influence of lifestyle factors affecting the inflammatory pathway, a possible causative mechanism. We will examine both persistent (present before and after diagnosis) and new-onset fatigue (lack of fatigue before diagnosis and development of fatigue after diagnosis). Strengths of the NHS dataset include data collected prospectively before and after diagnosis, availability of a comparable control group, and extensive information on dietary and lifestyle factors before and after diagnosis with an excellent follow-up rate. Although the cause of fatigue among cancer survivors is most likely multi-factorial, increasing evidence suggests that inflammation is an important mediator. Breast cancer survivors with fatigue have higher levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-1), and circulating T lymphocytes compared with survivors without fatigue. In addition, dietary intake can modify inflammatory biomarkers relating to cardiovascular disease and the metabolic syndrome. Therefore, if inflammation is a mediator of fatigue, lifestyle factors that modify inflammatory pathways may also influence fatigue among survivors. Using data both before and after cancer diagnosis for survivors and cancer-free comparisons, we propose analyses to characterize risk factors for persistent and new-onset fatigue among breast cancer survivors and lifestyle factors that may modify the development and persistence of fatigue. Our findings could lead to new methods of coping with a debilitating symptom and identifying women who might best respond to interventions to decrease fatigue. Our application is novel in examining dietary modifiers of fatigue. Specifically, we hypothesize that among breast cancer survivors that the prevalence of persistent fatigue is similar to that in matched controls without cancer, but that new-onset fatigue is more common among breast cancer survivors. We hope to identify predictors of new-onset, but not persistent, fatigue, such as age at diagnosis, employment status, and lack of physical activity and overweight at diagnosis. Finally, we will evaluate dietary modifiers of fatigue including a higher intake of cereal fiber, whole grains, and n-3 fatty acids and lower intake of saturated and trans-fatty acids. PUBLIC HEALTH RELEVANCE: Program narrative With over 2 million breast cancer survivors in the United States, we propose to evaluate the determinants of fatigue with a specific focus on new-onset and persistent fatigue among breast cancer survivors and an innovative exploration of dietary modifiers of fatigue.